Abstract
Aberrant signaling through insulin (Ins) and insulin-like growth factor I (IGF1) receptors contribute to the risk and advancement of many cancer types by activating cell survival cascades. Similarities between these pathways have thus far prevented the development of pharmacological interventions that specifically target either Ins or IGF1 signaling. To identify differences in early Ins and IGF1 signaling mechanisms, we developed a dual receptor (IGF1R & InsR) computational response model. The model suggested that ribosomal protein S6 kinase (RPS6K) plays a critical role in regulating MAPK and Akt activation levels in response to Ins and IGF1 stimulation. As predicted, perturbing RPS6K kinase activity led to an increased Akt activation with Ins stimulation compared to IGF1 stimulation. Being able to discern differential downstream signaling, we can explore improved anti-IGF1R cancer therapies by eliminating the emergence of compensation mechanisms without disrupting InsR signaling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antigens, CD / metabolism
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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Computational Biology
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Computer Simulation
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Female
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Genes, BRCA1
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Genes, BRCA2
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Humans
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Insulin / metabolism
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Insulin / pharmacology
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Insulin-Like Growth Factor I / metabolism
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Insulin-Like Growth Factor I / pharmacology
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MAP Kinase Signaling System / drug effects
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MCF-7 Cells
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Models, Biological*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism*
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / metabolism
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Receptor, Insulin / metabolism
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Ribosomal Protein S6 Kinases / antagonists & inhibitors*
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Signal Transduction / drug effects
Substances
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Antigens, CD
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IGF1 protein, human
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IGF1R protein, human
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Insulin
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Phosphoinositide-3 Kinase Inhibitors
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Insulin-Like Growth Factor I
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INSR protein, human
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Receptor, IGF Type 1
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Receptor, Insulin
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases